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Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in zebrafish.

ABSTRACT: Zebrafish (Danio rerio) have emerged as a popular model for studying the pharmacology and behavior of anxiety. While there have been numerous studies documenting the anxiolytic and anxiogenic effects of common drugs in zebrafish, many do not report or test for behavioral differences between the sexes. Previous studies have indicated that males and females differ in their baseline level of anxiety. In this study, we test for a sex interaction with fluoxetine and nicotine. We exposed fish to system water (control), 10 mg/L fluoxetine, or 1 mg/L nicotine for three minutes prior to being subjected to four minutes in an open-field drop test. Video recordings were tracked using ProAnalyst. Fish from both drug treatments reduced swimming speed, increased vertical position, and increased use of the top half of the open field when compared with the control, though fluoxetine had a larger effect on depth related behaviors while nicotine mostly affected swimming speed. A significant sex effect was observed where females swam at a slower and more constant speed than males, however neither drug produced a sex-dependent response.

SUBMITTER: Singer ML

PROVIDER: S-EPMC5012263 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in zebrafish.

Singer Matthew L ML Oreschak Kris K Rhinehart Zachariah Z Robison Barrie D BD

PeerJ 20160824

Zebrafish (Danio rerio) have emerged as a popular model for studying the pharmacology and behavior of anxiety. While there have been numerous studies documenting the anxiolytic and anxiogenic effects of common drugs in zebrafish, many do not report or test for behavioral differences between the sexes. Previous studies have indicated that males and females differ in their baseline level of anxiety. In this study, we test for a sex interaction with fluoxetine and nicotine. We exposed fish to syste ...[more]

PMID: 27635325

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Project description:The antidepressant fluoxetine (FLX), generally the first line of pharmacological treatment in adolescents and pregnant women with affective disorders, is an emerging endocrine disruptor that is also released to the environment through sewage. Recently, we demonstrated that FLX exposure during the first 6 days of life in zebrafish (ZF; Danio rerio) induced a male-specific reduction in the exploratory behavior in the adult ZF that was linked to a reduction in cortisol production that persisted across three generations. Here we investigated sex differences in the behavioral and stress responses following FLX (0.54 and 54 μg⋅L-1) exposure during two periods of sexual development in ZF; early (0-15 days post-fertilization, dpf) and late (15-42 dpf). Our findings revealed that the stress response in females was reduced compared to that of males independent of the treatment. We also found that FLX reduced total body cortisol levels in the adult ZF regardless of sex and window of exposure. The hypocortisol phenotype of our FLX-treated fish was associated with behavioral alterations in the adult fish, which depended on the window of exposure; males were more sensitive to FLX during early development whereas females were affected during late development. A sexually dimorphic behavioral response induced by the low cortisol phenotype was observed in the FLX-treated ZF; females had higher exploratory activity whereas the males had reduced behavior. In conclusion, FLX results in sex- and window of exposure-specific effects on the behavioral activities in adult ZF. These findings highlight the importance of sex differences and timing on the long-term effects of antidepressant treatments. Knowledge of the sex-specific effects of antidepressants and the importance of early life exposure to chemical stressors may help us understand the impact of highly prescribed drugs such as FLX on the fetus from FLX-treated pregnant women as well as aquatic species in environments receiving sewage effluents.

Project description:The zebrafish (Danio rerio) is an established model organism in pharmacology and biomedicine, including in research on alcohol use disorders and alcohol-related disease. In the past 2 decades, zebrafish has been used to study the complex effects of ethanol on the vertebrate brain and behavior in both acute, chronic and developmental exposure paradigms. Sex differences in the neurobehavioral response to ethanol are well documented for humans and rodents, yet no consensus has been reached for zebrafish. Here, we show for the first time that male zebrafish of the AB strain display more severe behavioral impairments than females for equal exposure concentrations. Adult zebrafish were immersed in 0, 1 or 2% (v/v) ethanol for 30 min, after which behavior was individually assessed in the zebrafish Multivariate Concentric Square Field™ (zMCSF) arena. Males exposed to 2% ethanol showed clear signs of sedation, including reduced activity, increased shelter seeking and reduced exploration of shallow zones. The 1% male group displayed effects in the same direction but of smaller magnitude; this group also explored the shallow areas less, but did not show a general reduction in activity nor an increase in shelter seeking. By contrast, 1 and 2% exposed females showed no alterations in explorative behavior. Females exposed to 2% ethanol did not display a general reduction in activity, rather activity gradually increased from hypoactivity to hyperactivity over the course of the test. This mixed stimulatory/depressant effect was only quantifiable when locomotory variables were analyzed over time and was not apparent from averages of the whole 30-min test, which may explain why previous studies failed to detect sex-specific effects on locomotion. Our results emphasize the importance of explicitly including sex and time as factors in pharmacological studies of zebrafish behavior. We hypothesize that the lower sensitivity of female zebrafish to ethanol may be explained by their greater body weight and associated larger distribution volume for ethanol, which may render lower brain ethanol concentrations in females.

Project description:Background: Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Methods: Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Results: Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Conclusion: Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.

Project description:ObjectiveStress exacerbates the pathophysiology of major neurodegenerative disorders. In this study, the zebrafish (Danio rerio), the frequently used model for experimental studies of stress and other central nervous system disorders, was used to evaluate the anxiolytic potential of flavonoids, namely silibinin and naringenin on alleviating acute stress-induced anxiety.Materials and methodsA molecular docking study with Molegro Virtual Docker software was done to assess the binding potential of flavonoids on serotonin and dopamine receptors. To determine the bioactivity and investigate the toxicity of the flavonoids, silibinin, and naringenin, brine shrimp lethality assay, and an acute toxicity study was conducted according to Organization for Economic Co-operation and Development (OECD) Test Guideline 203. The effect of silibinin and naringenin was assessed using behavioral tasks such as the novel tank assay and the light-dark test on the zebrafish model of acute stress.ResultsMolecular docking studies showed a higher affinity of silibinin and naringenin for the serotonin and dopamine receptors. In comparison to the LC50 value, 13.15 μg/ml of the reference standard potassium dichromate, silibinin, and naringenin yielded higher LC50 values, 34.10 μg/ml and 91.33 μg/ml, respectively. The LC50 value of silibinin and naringenin was observed to be >100 mg/l from the acute toxicity study on adult zebrafish. After transferring to a novel tank, silibinin and naringenin-treated zebrafish groups were found to explore the upper level of the tank, similar to standard drugs, and spent a long time in the upper level of the tank compared to the control group (p < 0.01). Both silibinin and naringenin treatment group spent increased amounts of time in the tank's illuminated part in contrast to that of the dark side as evidenced by the number of zebrafish entering or remaining in the illuminated part of the tank through the light-dark test. Silibinin and naringenin treated groups were found to spend increased time in the light side significantly on the day 15th of evaluation as compared to the control group (p < 0.05 and p < 0.001, respectively).ConclusionThe flavonoids, silibinin, and naringenin were found to mitigate acute stress-induced anxiety, owing to their anxiolytic properties in the zebrafish model and may be explored as the potential therapeutic agents for treating anxiety.

Dataset Information

Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in zebrafish.

Publications

Anxiolytic effects of fluoxetine and nicotine exposure on exploratory behavior in zebrafish.

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